Ibuprofen was first synthesized by Nicholson and Adamo in 1964, developed as a drug by Boots Pure Drug Co., Ltd., England, and has been utilized mainly as an antipyretic, analgesic and/or antiinflammatory agent. A phenylpropanolamine is a sympathomimetic drug having ephedrine-like pharmacological activities and therapeutic activities for nasal mucus and nasal congestion, and utilized as a drug for rhinitis in nonproprietary drugs.
In JP-A-61-501913 corresponding to WO85/04589, and in W091/17746, there are disclosed, for instance, pharmaceutical compositions of cold remedies comprising a nonsteroidal antiinflammatory agent such as ibuprofen and the like as an analgesic ingredient, phenylpropanolamine hydrochloride as a decongestive ingredient, dextromethorphan hydrobromide as an antitussive and chlorpheniramine maleate as an antihistamine. These pharmaceutical preparations are prepared by mixing dextromethorphan, ibuprofen and phenylpropanolamine hydrochloride directly with lactose and/or other base without being subjected to stabilization.
As a result of various investigations for preparing general cold remedies having more excellent actions, the present inventors found that pharmaceutical preparations comprising the dextromethorphan, the phenylpropanolamine (e.g. phenylpropanolamine hydrochloride, etc.) and further comprising ibuprofen are particularly favorable as cold remedies.
These pharmaceutical preparations, however, deteriorate or impair the stability of the active ingredients, and, thus, cause not only decrease of the effective amounts of the ingredients but also change of the external appearance with the lapse of time.
More precisely, it is confirmed that decomposition of phenylpropanolamine hydrochloride occurs by the reaction with some kinds of sugars, and by pH variation of a solution [R. H. Barry., J. Pharm. Sci., 71, No.1, Jan. 116-118, (1982)]. "Researches for incompatibility of pharmaceutical preparations" [Ueda, Report of Pharmacological Research Institute of Toyama Pref., Vol. 1984/1985, p127-234, (1987)] discloses that phenylpropanolamine hydrochloride is incompatible with lysozyme chloride, potassium guaiacolsulfonate, dextromethorphan hydrobromide and so on.
On the other hand, since ibuprofen has a lower melting point of 75.degree. C., when ibuprofen is coexisted with other ingredients, it may frequently cause melting point depression of the other ingredients. Further, a pharmaceutical composition comprising ibuprofen and other ingredient has low drug stability, thus it is liable to cause inactivation of active ingredients, change of external appearance and so on. For instance, "Incompatibility of ibuprofen granules" [Sato, Pharmacy, 27, 12, 73-78, (1976)] discloses that ibuprofen is incompatible with methylephedrine or sodium bicarbonate, and "Researches for incompatibility of pharmaceutical preparations" [Ueda, Report of Pharmacological Research Institute of Toyama Pref., Vol. 1984/1985, p127-234, (1987)] discloses that ibuprofen is incompatible with dl-chlorpheniramine maleate, ascorbic acid and so on.
Such problems as described above are particularly remarkable in a pharmaceutical preparation comprising a phenylpropanolamine, a dextromethorphan and ibuprofen. For example, in a pharmaceutical preparation containing dextromethorphan hydrobromide, ibuprofen and phenylpropanolamine hydrochloride as described in undermentioned Experimental Example 1, each of the ingredients is liable to be decomposed at a high temperature with the passage of time. Particularly, the stability of phenylpropanolamine hydrochloride is impaired and change of the external appearance occurs with incorporation of ibuprofen and dextromethorphan hydrobromide. Therefore, among pharmaceutical preparations comprising a dextromethorphan, ibuprofen, a phenylpropanolamine and the like, no successfully stabilized pharmaceutical preparation having adequate utility has been developed yet.